There has been a demand for the establishment of a technique for gene therapy on lymphoid cells in order to treat various diseases targeting lymphoid cells, e.g., human immunodeficiency virus (HIV) infection. However, no satisfactory vector system for introducing a desired gene into lymphoid cells has been developed.
Herpesvirus (HHV) is a generic term referring to viruses of the family Herpesviridae. Both human herpesvirus 6 and 7 (HHV-6 and HHV-7) are double-stranded DNA viruses of the subfamily β Herpesviridae of the family Herpesviridae, which are responsible for exanthem subitum. (Yamanishi K. et al., “Identification of human herpesvirus 6 as a casual agent for exanthem subitum”, Lancet 1988; i: 1065-1067 and Tanaka K. et al., “Human herpesvirus 7: Another casual agent for roseola (exanthem subitum)”, J. pediatr., 1994; 125: 1-5) HHV-6 includes two strains, HHV-6A and HHV-6B. HHV-6 causes a viral infectious disease which often occurs during infancy and induces sudden high fever and exanthema before and after the reduction of fever. Its prognosis is generally good. HHV-7 infection tends to occur later than HHV-6 infection (Tanaka K. et al., “Seroepidemiological study of human herpesvirus-6 and -7 in children of different ages and detection of those two viruses in throat swabs by polymerase chain reaction”, Journal of Medical Virology, 1996; 48: 88-94). Therefore, exanthem subitum caused by HHV-7 is clinically experienced as second exanthem subitum. A seroepidemiological study of HHV-6 and HHV-7 demonstrated that most children become positive for antibodies for HHV-6 and HHV-7 before the age of two or three. It has been reported that the inapparent infection rate is 20 to 40%.
HHV-7 is a herpesvirus which was newly found by Frenkel et al. in 1990 when a cytopathic effect occurred during culturing of CD4+ T lymphoid cells of a healthy person's peripheral blood (Frankel N. et al., “Isolation of a new herpesvirus from human CD4+ T cells”, ProNAS USA, 87: 749-752, ProNAS USA, 87: 749-752, 1990). The virus was isolated from mononuclear cells of human peripheral blood. Both HHV-6 and -7 are CD4+ T lymphoid cell tropic viruses. HHV-7 infects the cell via a CD4 receptor on the cell. HHV-7 can grow only in human T lymphoid cells. Therefore, HHV-7 is a virus which can be used for gene modification of human T lymphoid cells.
The HHV-7 genome is double-stranded DNA of about 145 kbp. The whole base sequence has been determined by Nicholas et al. It is known that at least 101 genes are present on the genome (John N. et al., Journal of Virology, September 1996, 5975 to 5989).
However, with respect to these HHVs, no detailed analysis has been conducted so far regarding the promoter activity thereof. Moreover, what is lymphoid cell specific for the viruses was due to the interaction with receptors in the cells, and the life cycle in which the viruses can only be propagated in human T-lymphocytes.
In addition, it is believed that these viruses, particularly HHV-7 virus, have no adverse effect on healthy persons. If a gene containing an antigenic determinant of various viruses (e.g., mumps) is incorporated into the viral genome of HHV-7 and is expressed in HHV-7, HHV-7 is considered to be useful as a vaccine. However, when HHV-7 is used as a vaccine, it is not preferable that the genotype is changed as the virus is subcultured, in terms of quality control and quality assurance. Therefore, when the recombinant virus is used as a vaccine, it is necessary to stably supply a virus derived from a single recombinant genotype virus. For this purpose, a technique for producing a HHV-7 recombinant virus having a single genotype has been desired.
In addition, the mutual relationship between the HIV infection of a T lymphoid cell strain SupT1 cell and a T lymphoid cell tropic human herpesvirus (HHV-6A (U1102 strain), HHV-7 (MRK, MSO strains)) has been studied. The HHV-7 strain, which is bound by a CD4 receptor of cells, exhibits satisfactory growth in SupT1 cells. However, infection could not been established for SupT1/HIV cells. In contrast, it has been recognized that the HHV-6A strain infects HIV-persistent infection SupT1 (SupT1/HIV) cells and exhibits clear CPE (Masao Yamada et al., “HIV Jizokukansen SupT1 Saibo heno HHV-6 oyobi-7 Choufukukannsen no Kokoromi (Attempt for HHV-6 and -7 Superinfection to HIV Persistent Infection Sup-T1 Cell)”, Title No. 122, Titles and Abstracts of the 7th Annual Meeting of the Japanese Society for AIDS Research, 1993, Tokyo).
An ideal HIV vaccine can provide perfect and long-term protection from all types of HIV. On the other hand, conventional inactivated HIV vaccines have advantages and disadvantages, some of which will be described below. A method for producing a recombinant vaccine employs common techniques. However, since it is difficult to maintain immunogenicity (since immunogenicity is low), high antigenic load and frequent inoculation of an adjuvant are required. Safety is the greatest concern. A subunit vaccine containing either a native or recombinant subunit may be safe. However, such a subunit vaccine requires high antigen load and frequent vaccination with adjuvant, because of the use of a subunit and the low immunogenicity. Moreover, safety is the most important issue. Furthermore, subunit vaccines comprising either a native or a recombinant subunit may be safe, however, they are subjected to limitation due to low selectivity and low immunogenicity of the subunit, thereby they allow development of usable vaccines for treating an immune responsible cell such as HIV vaccines and the like.    [non-patent literature 1] Yamanishi K et al., “Identification of human herpesvirus 6 as a casual agent for exanthem subitum.” Lancet 1988; i: pp. 1065-1067    [non-patent literature 2] Tanaka K et al., “Human herpesvirus 7: Another casual agent for roseola (exanthem subitum)” J pediatr. 1994; 125: pp. 1-5    [non-patent literature 3] Tanaka-Taya K et al., “Seroepidemiological study of human herpesvirus-6 and -7 in children of different ages and detection of those two viruses in throat swabs by polymerase chain reaction” Journal of Medical Virology. 1996; 48: pp. 88-94    [non-patent literature 4] Frankel N et al., “Isolation of a new herpesvirus from human CD4+T cells.” ProNAS USA 87:749-752, ProNAS USA 87:749-752, 1990    [non-patent literature 5] John N. et al., Journal of Virology, Sep. 1996, pp. 5975-5989    [non-patent literature 6] Masao Yamada et al., “HIV Jizokukansen SupT1 Saibo heno HHV-6 oyobi -7 Choufukukannsen no Kokoromi (Attempt for HHV-6 and -7 Superinfection to HIV Persistent Infection Sup-T1 Cell)”, Title No. 122, Titles and Abstracts of the 7th Annual Meeting of the Japanese Society for AIDS Research, 1993, Tokyo